As described elsewhere in this supplement, development of effective methods for prevention of human immunodeficiency virus (HIV) infection has proven to be more challenging than development of effective treatment for the disease. New strategies to control the HIV epidemic are urgently needed; this urgency creates interest in investigation of the possibility of using antiretroviral treatment in combination with other modalities to control the epidemic. This article summarizes current knowledge concerning prevention modalities in the context of the drivers of the HIV epidemic in specific communities, describes challenges in investigating test-and-treat strategies, and proposes research directions for addressing these challenges to investigate the impact of prevention strategies on mitigation of epidemics.